WO2019045452A1 - TNFα 관련 질환을 치료하는 방법 - Google Patents

TNFα 관련 질환을 치료하는 방법 Download PDF

Info

Publication number
WO2019045452A1
WO2019045452A1 PCT/KR2018/009998 KR2018009998W WO2019045452A1 WO 2019045452 A1 WO2019045452 A1 WO 2019045452A1 KR 2018009998 W KR2018009998 W KR 2018009998W WO 2019045452 A1 WO2019045452 A1 WO 2019045452A1
Authority
WO
WIPO (PCT)
Prior art keywords
antibody
weeks
antigen
binding fragment
patient
Prior art date
Application number
PCT/KR2018/009998
Other languages
English (en)
French (fr)
Korean (ko)
Inventor
김선정
서지혜
안현철
이성영
Original Assignee
(주)셀트리온
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to JP2020512018A priority Critical patent/JP2020532520A/ja
Priority to CN201880055961.9A priority patent/CN111094342A/zh
Application filed by (주)셀트리온 filed Critical (주)셀트리온
Priority to EP18852415.1A priority patent/EP3677596A4/en
Priority to US16/643,377 priority patent/US20210371510A1/en
Priority to MX2020002278A priority patent/MX2020002278A/es
Priority to SG11202001739YA priority patent/SG11202001739YA/en
Priority to AU2018326037A priority patent/AU2018326037A1/en
Priority to CU2020000015A priority patent/CU20200015A7/es
Priority to EA202090544A priority patent/EA202090544A1/ru
Priority to CR20200095A priority patent/CR20200095A/es
Priority to BR112020003951-9A priority patent/BR112020003951A2/pt
Priority to JOP/2020/0046A priority patent/JOP20200046A1/ar
Priority to CA3074168A priority patent/CA3074168A1/en
Publication of WO2019045452A1 publication Critical patent/WO2019045452A1/ko
Priority to CONC2020/0002117A priority patent/CO2020002117A2/es
Priority to PH12020550066A priority patent/PH12020550066A1/en
Priority to DO2020000049A priority patent/DOP2020000049A/es
Priority to IL272977A priority patent/IL272977A/en
Priority to ZA2020/01927A priority patent/ZA202001927B/en
Priority to JP2023196788A priority patent/JP2024023347A/ja

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/241—Tumor Necrosis Factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/655—Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/51—Complete heavy chain or Fd fragment, i.e. VH + CH1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/515—Complete light chain, i.e. VL + CL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin

Definitions

  • the present application relates to a method of subcutaneously administering an antibody (anti-TNFa antibody) that binds to TNFa to treat a TNFa related disease.
  • an antibody anti-TNFa antibody
  • Tumor necrosis factor alpha is a cellular signaling protein (cytokine) that is involved in systemic inflammation, and is one of the cytokines that form an acute phase response.
  • TNFa is associated with a variety of diseases and disorders including sepsis, infections, autoimmune diseases and graft rejection. TNFa promotes an immune response which causes many clinical problems associated with autoimmune disorders such as rheumatoid arthritis, ankylosing spondylitis, ulcerative colitis, adult Crohn's disease, paediatrics, psoriasis and psoriatic arthritis. This abnormality can be treated by using a TNFa inhibitor.
  • Infliximab is a kind of chimeric monoclonal antibody capable of acting as a TNFa inhibitor.
  • Remixima, Remicade, Renflexis and the like are currently on the market. However, All of these products are made from lyophilized powder, which is reintroduced and diluted, and injected intravenously according to the dosage and dosage of each disease.
  • the intravenous administration method as described above requires a patient to visit the hospital for medication and takes 2 to 4 hours including the waiting time, which is a considerable burden and inconvenience in daily life.
  • the applicant is limited to a person who has received medical education.
  • SC subcutaneous
  • Subcutaneous administration can reduce the administration time from 2 to 5 minutes, which is 30 to 90 minutes, .
  • Rituxan (Rituximab), Simponi (Golimumab), Herceptin (Herceptin), etc. have also been developed and marketed as agents for subcutaneous administration together with intravenous and subcutaneous agents. Trastuzumab), Actemra (Tocilizumab), and Xolair (Omalizumab). However, there is no formulation for subcutaneous administration of infliximab.
  • the present applicant has demonstrated the efficacy and stability equivalent to those of existing intravenous administration upon subcutaneous administration of the infliximag formulation, and completed a subcutaneous administration therapy which improves patient convenience and improves quality of life.
  • the object of the present invention is to provide a therapeutic method for subcutaneously administering a pharmaceutical composition containing an anti-TNF ⁇ antibody or an antigen-binding fragment thereof to a subject for the treatment of TNF ⁇ -related diseases.
  • Another object to be solved by the present invention is to provide a pharmaceutical composition containing an anti-TNFa antibody or an antigen-binding fragment thereof and being subcutaneously administered to a subject, for the treatment of a disease treatable with an anti-TNFa antibody.
  • Another object to be solved by the present invention is to provide a use of an anti-TNFa antibody or an antigen-binding fragment thereof in the manufacture of a medicament for the treatment of a disease treatable with an anti-TNFa antibody by subcutaneous administration to a subject.
  • the present invention provides a method of treating a disease treatable with an anti-TNFa antibody, comprising subcutaneously administering to a subject a pharmaceutical composition containing an anti-TNF [alpha] antibody or antigen-binding fragment thereof.
  • the invention also provides a pharmaceutical composition for the treatment of a disease treatable with an anti-TNFa antibody, comprising an anti-TNFa antibody or antigen-binding fragment thereof and administered subcutaneously to a subject.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising (a) an anti-TNFa antibody or antigen-binding fragment thereof and a pharmaceutically acceptable carrier; And (b) instructions for directing subcutaneous administration of the pharmaceutical composition to a subject to treat a disease treatable with the anti-TNFa antibody.
  • the invention also provides the use of an anti-TNFa antibody or antigen-binding fragment thereof in the manufacture of a pharmaceutical composition for the treatment of a disease treatable with an anti-TNFa antibody, which is subcutaneously administered to a subject.
  • the anti-TNFa antibody may comprise one or more selected from the group consisting of infliximag, adalimumab, sertoliumpergol, golimumap, and biosimilars thereof.
  • the anti-TNFa antibody may be an infliximab.
  • the anti-TNFa antibody may comprise a chimeric human-murine IgG monoclonal antibody.
  • the anti-TNFa antibody comprises a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 1, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 2, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3 Light chain variable region; And a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 5, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 6.
  • the anti-TNFa antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7; And a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 8.
  • the anti-TNFa antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 9; And a heavy chain comprising the amino acid sequence of SEQ ID NO: 10.
  • the composition comprises a surfactant; A sugar or a derivative thereof; And a buffer comprising acetate or histidine.
  • the composition may comprise polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or mixtures thereof as a surfactant.
  • the surfactant concentration of the composition may be from 0.02 to 0.1% (w / v).
  • the composition may comprise sorbitol, mannitol, trehalose, sucrose or mixtures thereof as a sugar or derivative thereof.
  • the sugar or derivative concentration of the composition may be between 1 and 10% (w / v).
  • the composition may comprise acetate as a buffer.
  • the buffer concentration of the composition may be between 1 and 50 mM.
  • the pH of the composition may be 4.0 to 5.5.
  • the composition comprises (A) between 90 and 180 mg / ml anti-TNFa antibody; (B) 0.02 to 0.1% (w / v) polysorbate; (C) 1 to 10% (w / v) of sorbitol; And (D) 1 to 50 mM of a buffer comprising acetate or histidine.
  • the composition may not comprise aspartic acid, lysine, arginine, or mixtures thereof.
  • the composition may not comprise NaCl, KCl, NaF, KBr, NaBr, Na2SO4, NaSCN, K2SO4 or mixtures thereof.
  • the composition may not contain a chelating agent.
  • the composition may have a viscosity of 0.5 cp to 10.0 cp after one month at 40 ° C ⁇ 2 ° C, or a viscosity of 0.5 cp to 5 cp after 6 months at a temperature of 5 ° C ⁇ 3 ° C.
  • the composition may not undergo a reconstitution step, a dilution step or both before use.
  • the composition can be administered to a subject by being filled in a pre-filled syringe or auto-injector.
  • the subject may comprise a mammal.
  • the subject may comprise a person.
  • 60 to 300 mg of the antibody or antigen-binding fragment thereof may be administered.
  • the antibody or antigen-binding fragment thereof is selected from the group consisting of 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, , 240, 250, 260, 270, 280, 290 or 300 mg.
  • 90 to 180 mg of the antibody or antigen-binding fragment thereof may be administered.
  • the antibody or antigen-binding fragment thereof may be administered in an amount of 120 to 240 mg.
  • the antibody or antigen-binding fragment thereof may be administered in an amount of 80 to 100 mg, 110 to 130 mg, 170 to 190 mg or 230 to 250 mg.
  • the antibody or antigen-binding fragment thereof may be administered at 90 mg, 120 mg, 180 mg or 240 mg.
  • the antibody or antigen-binding fragment thereof may be administered in an amount of 90 to 180 mg, or in the case of 80 kg or more, 190 to 270 mg.
  • the antibody or antigen-binding fragment thereof may be administered at intervals of 1 to 8 weeks.
  • the antibody or antigen-binding fragment thereof may be administered at 1, 2, 3, 4, 5, 6, 7 or 8 weeks apart.
  • the antibody or antigen-binding fragment thereof may be administered at intervals of 2 or 4 weeks.
  • the diseases treatable with anti-TNF [alpha] antibodies may include rheumatoid arthritis, ulcerative colitis, Crohn's disease, scleroderma, psoriatic arthritis and ankylosing spondylitis.
  • the subject to be treated with an anti-TNFa antibody may comprise one or more characteristics selected from the following.
  • DMARDs disease-modifying anti-rheumatic drugs
  • the patient can be a patient who has been intravenously administered at least once before the subcutaneous administration, an anti-TNF [alpha] antibody or antigen-binding fragment thereof.
  • the patient may be a patient receiving intravenously 1 to 10 mg / kg of anti-TNFa antibody or antigen-binding fragment thereof, before subcutaneous administration.
  • initial subcutaneous administration may be performed at 2 to 8 weeks after the final intravenous administration.
  • initial subcutaneous administration may be performed at 4 weeks after the final intravenous administration.
  • the composition comprising an anti-TNF [alpha] antibody or antigen-binding fragment thereof is administered in combination with one or more doses selected from the group consisting of infliximim, adalimumar, sertolium mapulol, , Before, or after administration.
  • the composition comprising an anti-TNF [alpha] antibody or antigen-binding fragment thereof is administered prior to or after administration of methotrexate, leflunomide and sulfasalazine, hydroxychloroquine or a combination thereof .
  • the patient after subcutaneous administration may comprise one or more of the following characteristics.
  • CDAI Crohn's disease activity index
  • the therapeutic method, composition, kit or use according to the present invention can treat TNFa related diseases by subcutaneously administering an anti-TNFa antibody or an antigen-binding fragment thereof.
  • the therapeutic method, composition, kit or use according to the present invention is advantageous in that the time taken for administration is reduced and the time for patients staying in the hospital is reduced compared to intravenous injection, thereby improving patient convenience through improvement of convenience and quality of life to provide.
  • the therapeutic method, composition, kit or use according to the present invention is added as a new treatment option of Infliximab to provide patients and health care workers who have received infliximab intravenously in the past with benefits .
  • Figure 1 shows a design outline of an infliximab subcutaneous administration clinical trial in rheumatoid arthritis (RA) patients.
  • Figure 2 shows a design summary of an infliximab subcutaneous administration study in patients with Crohn's disease (CD).
  • the present invention relates to a method of treating a disease treatable with an anti-TNFa antibody comprising subcutaneously administering to a subject a pharmaceutical composition containing an anti-TNFa antibody or antigen-binding fragment thereof.
  • TNFa refers to a human cytokine consisting of a trimer in which the biologically active form is 17 kD secreted form and 26 kD membrane associated form non-covalently bound to a 17 kD molecule .
  • the structure of TNF [alpha] is also described, for example, in Pennica, D., et al. (1984) Nature 312: 724-729; Davis, J. M., et al. (1987) Biochemistry 26: 1322-1326; And Jones, E. Y., et al. (1989) Nature 338: 225-228.
  • Antibody refers to an immunoglobulin molecule consisting of four polypeptide chains in which two heavy chains and two light chains are linked to each other by disulfide bonds. Other naturally occurring antibodies with altered structures, such as camelid antibodies, are also included in this definition.
  • Each heavy chain consists of a heavy chain variable region and a heavy chain constant region.
  • the heavy chain constant region consists of three domains (CH1, CH2 and CH3).
  • Each light chain consists of a light chain variable region and a light chain constant region.
  • the light chain constant region consists of one domain (CL).
  • the heavy chain variable region and the light chain variable region can be further subdivided into a hypervariable region called the complementarity determining region (CDR), which is disposed with a more conserved region called the framework region (FR).
  • CDR complementarity determining region
  • FR framework region
  • Each heavy chain variable region and light chain variable region consists of three CDRs and four FRs, arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • an "antigen binding fragment” refers to one or more fragments of an antibody that retain the ability to specifically bind to the antigen bound by the complete antibody.
  • exemplary antigen binding fragments include, but are not limited to, Fab, Fab ', F (ab') 2, Fv, and the like.
  • Biosimilar refers to a biological product that is very similar to an FDA-approved biological product (reference drug) and has no clinically significant difference from the reference product in terms of pharmacokinetics, safety and efficacy. do.
  • Administration refers to administration of a substance (e. G., An anti-TNFa antibody) to achieve therapeutic purposes, such as a TNFa related disorder.
  • a substance e. G., An anti-TNFa antibody
  • TNFa related disorder refers to a local and / or systemic physiological disorder in which TNFa is a major mediator of inducing signs of disease.
  • the terms &quot; TNFa related disease &quot;, &quot; disease treatable with anti-TNFa &quot;, and &quot; diseases where the activity of TNFa is detrimental &quot; are used interchangeably herein.
  • Subject includes all human or non-human animals.
  • non-human animal includes vertebrate animals such as non-human primates, sheep, cats, rabbits and ferrets, rodents such as mice, rats and guinea pigs, bird species such as chicken, amphibians and reptiles However, it is not limited thereto.
  • the subject is a mammal such as a non-human primate, sheep, dog, cat, rabbit, ferret or rodent.
  • the subject is human (person).
  • subject ", " patient " and “ subject " are used interchangeably herein.
  • IC50 is intended to refer to the concentration of inhibitor required to inhibit the desired biological outcome, e. G., To neutralize cytotoxic activity.
  • Kit refers to a packaged product comprising components for administering a TNFa antibody of the invention for the treatment of a TNFa related disorder.
  • the kit preferably comprises a container or box that holds the components of the kit.
  • the box or container shall be accompanied by a protocol or label approved by the Food and Drug Administration.
  • the box or container holds the components of the present invention contained within a plastic, polyethylene, polypropylene, ethylene or propylene container.
  • the container may be a tube or bottle with a lid.
  • the kit also includes instructions for administration of the TNFa antibody of the invention.
  • the antibody may comprise a polyclonal antibody, a monoclonal antibody, a recombinant antibody, a single chain antibody, a hybrid antibody, a chimeric antibody, a humanized antibody or a fragment thereof.
  • a chimeric antibody refers to an antibody comprising a constant region sequence from a species different from the heavy and light chain variable region sequences from either species.
  • chimeric human-mouse IgG monoclonal antibodies can be included as antibodies.
  • the chimeric human-murine IgG monoclonal antibody consists of the mouse heavy and light chain variable regions and the human heavy and light chain constant regions linked thereto.
  • Chimeric human-mouse IgG monoclonal antibodies can be prepared by methods known in the art. For example, in the case of infliximab, it can be prepared by the method described in U.S. Patent No. 6,284,471.
  • the antibody may comprise an antibody that binds to an epitope of TNF [alpha] or TNF [alpha].
  • Antibodies that bind to an epitope of TNFa or TNFa may include one or more selected from the group consisting of infliximag, adalimumab, sertolium mappalol, golimumab, and biosimilars thereof. In one embodiment of the invention, it may comprise an infliximap as an antibody.
  • the antibody or antigen-binding fragment thereof comprises a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 1, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 2, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: A light chain variable region comprising a light chain variable region; And a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 5, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 6.
  • the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7; And a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 8.
  • the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 9; And a heavy chain comprising the amino acid sequence of SEQ ID NO: 10.
  • &quot a composition comprising an anti-TNF [alpha] antibody or antigen-binding fragment thereof of the invention &quot; is used interchangeably with a &quot; stable liquid pharmaceutical preparation &quot;.
  • a composition according to the present invention comprises (A) an antibody or antigen-binding fragment thereof; (B) a surfactant; (C) a sugar or derivative thereof; And (D) a buffer.
  • &quot not comprising &quot; in the specification of the present application means not containing any of the components. It is also to be understood that the term encompasses those that do not substantially contain the component, i. E., The activity of the antibody, the stability and viscosity of the liquid pharmaceutical formulation, for example, the total weight of the liquid pharmaceutical formulation (W / v), 0 to 1 ppm (w / v) or 0 to 1 ppb (w / v) by reference.
  • composition according to the invention may, in one embodiment, comprise an anti-TNFa antibody of the invention or an antigen-binding fragment thereof as described above.
  • the concentration of the antibody or antigen-binding fragment thereof can be freely adjusted within a range that does not adversely affect the stability and viscosity of the composition according to the present invention.
  • the concentration of the antibody or antigen-binding fragment thereof may be 10 to 200 mg / mL.
  • the concentration of the antibody or antigen-binding fragment thereof may be 50 to 200 mg / mL.
  • the concentration of the antibody or antigen-binding fragment thereof may be 80-150 mg / mL.
  • the concentration of the antibody or antigen-binding fragment thereof may be 90 to 145 mg / mL.
  • the concentration of the antibody or antigen-binding fragment thereof may be between 110 and 130 mg / mL.
  • concentration of the antibody or antigen-binding fragment thereof is within this range, the degree of freedom of the administration dose and the administration period can be increased according to the high content of the antibody or antigen-binding fragment thereof, and long term stability and low viscosity can be excellently shown.
  • surfactants include polyoxyethylene sorbitan fatty acid esters (e.g., polysorbates), polyoxyethylene alkyl ethers (e.g., Brij), alkylphenyl polyoxyethylene ethers (e.g., Triton-X) But are not limited to, polyoxyethylene-polyoxypropylene copolymers (e.g., Poloxamer, Pluronic), sodium dodecyl sulfate (SDS), and the like.
  • polyoxyethylene sorbitan fatty acid esters e.g., polysorbates
  • polyoxyethylene alkyl ethers e.g., Brij
  • alkylphenyl polyoxyethylene ethers e.g., Triton-X
  • polyoxyethylene-polyoxypropylene copolymers e.g., Poloxamer, Pluronic
  • SDS sodium dodecyl sulfate
  • the surfactant may comprise a polyoxyethylene sorbitan fatty acid ester (polysorbate).
  • Polysorbate may include polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or a mixture of two or more thereof.
  • the polysorbate may comprise polysorbate 20, polysorbate 80 or mixtures thereof.
  • the polysorbate may comprise polysorbate 80.
  • the concentration of the surfactant can be freely adjusted within a range that does not adversely affect the stability and viscosity of the stable liquid pharmaceutical preparation according to the present invention.
  • the concentration of the surfactant may be 0.001 to 5% (w / v), 0.01 to 1% (w / v), or 0.02 to 0.1% (w / v).
  • the concentration of the surfactant is within this range, excellent long-term stability and low viscosity can be obtained.
  • the sugar may include monosaccharides, disaccharides, oligosaccharides, polysaccharides or a mixture of two or more thereof.
  • monosaccharides include, but are not limited to, glucose, fructose, galactose, and the like.
  • disaccharides include, but are not limited to, sucrose, lactose, maltose, trehalose, and the like.
  • oligosaccharides include, but are not limited to, fructooligosaccharides, galactooligosaccharides, and mannanoligosaccharides.
  • polysaccharides include, but are not limited to, starch, glycogen, cellulose, chitin, pectin, and the like.
  • the derivatives of sugars may include sugar alcohols, sugar acids or mixtures thereof.
  • sugar alcohols include glycerol, erythritol, traceol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, bolemitol, isomalt, maltitol, lactitol, maltotriol , Maltotetriol, polyglycitol, and the like.
  • saccharic acid examples include, but are not limited to, aldonic acid (such as glyceric acid), wolloxic acid (such as neuraminic acid), uronic acid (such as glucuronic acid), and aldaric acid (such as tartaric acid)
  • aldonic acid such as glyceric acid
  • wolloxic acid such as neuraminic acid
  • uronic acid such as glucuronic acid
  • aldaric acid such as tartaric acid
  • sugars or derivatives thereof may include sorbitol, mannitol, trehalose, sucrose or a mixture of two or more thereof.
  • the concentration of the sugar or derivative thereof can be freely adjusted within a range that does not substantially adversely affect the stability and viscosity of the liquid pharmaceutical formulation according to the present invention.
  • the concentration of the sugar or derivative thereof may be 0.1 to 30% (w / v), 1 to 20% (w / v) or 1 to 10% (w / v).
  • concentration of the sugar or its derivative is within this range, excellent long-term stability and low viscosity can be obtained.
  • the buffering agent is a neutralizing substance that minimizes the pH change due to acid or alkali.
  • the buffering agent include phosphate, acetate, succinate, gluconate, glutamate, Citrate, histidine, and the like.
  • the buffer may comprise acetate or histidine. Stability may be impaired if both acetate and histidine are included as buffering agents.
  • the buffer may comprise acetate.
  • the acetate include, but are not limited to, sodium acetate, zinc acetate, aluminum acetate, ammonium acetate, and potassium acetate.
  • an acid for example acetic acid, may additionally be included.
  • the inclusion of acetate as a buffer may be most desirable in terms of pH control and stability.
  • the buffer may comprise histidine.
  • histidine salt such as histidine chloride, histidine acetate, histidine phosphate, histidine sulfate and the like may be included.
  • acids such as hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid, and the like.
  • the stable liquid pharmaceutical formulation may not comprise citrate (citrate), phosphate (phosphate) or a mixture thereof.
  • the content of the buffer (or an anion of the buffer) can be freely adjusted within a range that does not substantially adversely affect the stability and viscosity of the liquid pharmaceutical formulation according to the present invention.
  • the content of the buffer or its anion may be 1 to 50 mM, 5 to 30 mM or 10 to 25 mM. When the content of the buffering agent or its anion is within this range, excellent long-term stability and low viscosity can be obtained.
  • the pH of the stable liquid pharmaceutical composition may be 4.0 to 5.5 or 4.7 to 5.3.
  • the pH can be adjusted using a buffer.
  • the buffering agent when the buffering agent is contained in a predetermined amount, the pH in the above range can be exhibited without a separate pH adjusting agent.
  • citrate, phosphate or a mixture thereof is used as a buffer, it may be difficult to show a pH in the above range.
  • the stability of the antibody may be degraded if it further comprises an acid (e.g., hydrochloric acid) or a base (e.g., sodium hydroxide) as a separate pH adjusting agent.
  • the stable liquid pharmaceutical formulation may not contain aspartic acid, lysine, arginine, or mixtures thereof. When these amino acids are included, the preparation can be in a solid state. In one embodiment of the invention, the stable liquid pharmaceutical formulation may comprise one or more of the remaining amino acids except for the three amino acids. In this case, the amino acid may be used in an amount within the range of 5% (w / v), for example, 0.001 to 5% (w / v), 0.001 to 1% (w / v), in the range of 0.01 to 1% (w / v), in the range of 0.1 to 5% (w / v), or in the range of 0.1 to 1% (w / v).
  • the stable liquid pharmaceutical formulation may comprise taurine.
  • the taurine may be used in an amount within a range of 5% (w / v), for example, 0.001 to 5% (w / v), 0.001 to 1% (w / v), in the range of 0.01 to 1% (w / v), in the range of 0.1 to 5% (w / v), or in the range of 0.1 to 1% (w / v).
  • the stable liquid pharmaceutical formulation may be a metal salt does not include NaCl, KCl, NaF, KBr, NaBr, Na 2 SO 4, NaSCN, K 2 SO 4.
  • metal salts When these metal salts are included, precipitation occurs and the preparation may have the shape of gelatin and the stability may be poor.
  • the stable liquid pharmaceutical formulation may not contain a chelating agent (e.g., EDTA).
  • a chelating agent e.g., EDTA
  • the inclusion of a chelating agent may increase the oxidation rate.
  • the stable liquid pharmaceutical agent may not contain a preservative.
  • preservatives include octadecyldimethylbenzylammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl alcohol, benzyl alcohol, alkyl paraben, catechol, resorcinol, cyclohexanol, M-cresol, and the like. Containing a preservative may not help to improve stability.
  • the stable liquid pharmaceutical preparation of the present invention may further comprise additives known in the art within the scope of substantially not adversely affecting the activity of the antibody, stability and low viscosity of the formulation have.
  • an aqueous carrier for example, an aqueous carrier, an antioxidant, or a mixture of two or more thereof.
  • Aqueous carriers are those that are pharmaceutically acceptable (safe and non-toxic for administration to humans) and useful for the preparation of liquid pharmaceutical preparations.
  • aqueous carriers include, but are not limited to, sterile water for injection (SWFI), bacteriostatic water for injection (BWFI), sterile saline solution, Ringer's solution, dextrose, and the like.
  • Antioxidants include, but are not limited to, ascorbic acid.
  • stable in a &quot; stable &quot; liquid pharmaceutical formulation of the present invention means that the antibody according to the present invention substantially retains its physical stability and / or chemical stability and / or biological activity during the manufacturing process and / .
  • a variety of analytical techniques for measuring antibody stability are readily available in the art.
  • the physical stability can be assessed by methods known in the art, including the measurement of sample apparent attenuation of light (absorbance or optical density). This light attenuation measurement is related to the turbidity of the formulation. Further, high molecular weight component content, low molecular weight component content, intact protein amount, and insoluble foreign particle number can be measured with respect to physical stability.
  • Chemical stability can be assessed, for example, by detecting and quantifying chemically altered forms of the antibody.
  • Chemical stability includes, for example, charge changes that may be assessed by ion exchange chromatography (such as occurs as a result of deamidation or oxidation).
  • charge modifications acidic or basic peaks
  • chemical stability charge modifications (acidic or basic peaks) and the like can be measured.
  • Bioactivity can be assessed by methods known in the art and antigen binding affinity can be determined, for example, by ELISA.
  • the liquid pharmaceutical formulation can be stable for a long period of time.
  • liquid pharmaceutical formulation means a liquid pharmaceutical formulation that satisfies one or more of the following:
  • a liquid pharmaceutical formulation having an absorbance A 600 of 0 to 0.0300 or 0 to 0.0700 as measured by a spectrophotometer after storage for 4 weeks at a temperature of 40 ° C ⁇ 2 ° C;
  • a liquid pharmaceutical formulation having a temperature of 40 ° C ⁇ 2 ° C, a relative humidity of 75 ⁇ 5% and an absorbance A 600 as measured by a spectrophotometer after storage for 4 weeks in an airtight condition of 0 to 0.0300 or 0 to 0.0700;
  • a liquid pharmaceutical formulation having a main component of 98% to 100% as measured by SE-HPLC after storage at 40 ° C ⁇ 2 ° C for 4 weeks;
  • liquid pharmaceutical formulation having a temperature of 40 ° C ⁇ 2 ° C, a relative humidity of 75 ⁇ 5% and a main component of 98-100% as measured by SE-HPLC after storage for 4 weeks under confined conditions;
  • liquid pharmaceutical formulation having a temperature of 5 ° C ⁇ 3 ° C and a high molecular weight component as measured by SE-HPLC after storage for 12 months under confined conditions of 0-1.00%;
  • liquid pharmaceutical formulation having a low molecular weight component as measured by SE-HPLC after storage for 12 months at a temperature of 5 ° C ⁇ 3 ° C of 0 to 0.40%;
  • liquid pharmaceutical formulation having a low molecular weight component as measured by SE-HPLC of 0 to 0.40% after storage at 5 ° C ⁇ 3 ° C for 12 months under closed conditions;
  • liquid pharmaceutical preparations having a temperature of 5 ° C ⁇ 3 ° C and a number of insoluble foreign particles (10.00 ⁇ m ⁇ , ⁇ 400.00 ⁇ m) as measured by HIAC after storage for 12 months under confined conditions from 0 to 1,000;
  • a liquid medicine having a temperature of 40 ° C ⁇ 2 ° C, a relative humidity of 75 ⁇ 5% and a number of insoluble foreign particles (1.00 ⁇ m ⁇ , ⁇ 100.00 ⁇ m) measured by MFI after storage for 4 weeks in an airtight condition, Agents;
  • liquid pharmaceutical preparations having a number of insoluble foreign particles (10.00 [mu] m, ⁇ 100.00 [mu] m) measured by MFI after storage for 4 weeks at a temperature of 40 [deg.] C +/- 2 deg.
  • a liquid pharmaceutical formulation having a temperature of 40 ° C ⁇ 2 ° C, a relative humidity of 75 ⁇ 5% and an oxidation rate of the heavy chain Met 255 measured by LC-MS after storage for 4 weeks in an airtight condition of 0% to 2.5%;
  • liquid pharmaceutical formulation having an acidic peak of 20% to 35% as measured by IEC-HPLC after storage at 40 ° C ⁇ 2 ° C for 4 weeks;
  • a liquid pharmaceutical formulation having a temperature of 40 ° C ⁇ 2 ° C, a relative humidity of 75 ⁇ 5% and an acidic peak as measured by IEC-HPLC of 20% to 35% after storage for 4 weeks in an airtight condition;
  • a liquid pharmaceutical formulation having a temperature of 40 ° C ⁇ 2 ° C, a relative humidity of 75 ⁇ 5% and a basic peak as measured by IEC-HPLC of 33% to 40% after storage for 4 weeks in an airtight condition;
  • liquid pharmaceutical formulation having a TNF ⁇ binding affinity of 80% to 120% as measured by ELISA after storage at 5 ° C ⁇ 3 ° C for 12 months;
  • liquid pharmaceutical formulation having a TNF ⁇ binding affinity of 80% to 120% as measured by ELISA after storage at 5 ° C ⁇ 3 ° C for 12 months under confined conditions.
  • the viscosity measured after one month at a temperature of 40 ° C ⁇ 2 ° C may be between 0.5 cp and 10.0 cp. In another embodiment of the present invention, the viscosity measured after 6 months at a temperature of 5 ⁇ 3 ⁇ may be between 0.5 cp and 5.0 cp.
  • a liquid pharmaceutical preparation can be prepared by adding a buffer to a solution containing a surfactant and sugar or a derivative thereof, adjusting the pH thereof, and then adding the antibody to the mixed solution. Further, in the final stage of the purification process, a liquid pharmaceutical preparation may be prepared by preparing a solution containing some excipients and then adding the remaining components. For example, a liquid pharmaceutical preparation can be prepared by preparing a solution containing an antibody, a buffer, and a sugar or a derivative thereof at the final stage of the purification process, and then adding a surfactant to the solution.
  • the preparation may not include a lyophilization process in manufacture, or may include a lyophilization process.
  • liquid pharmaceutical preparation of the present invention can be prepared and placed in an airtight container immediately after the treatment such as sterilization.
  • liquid pharmaceutical preparation of the present invention is prepared and lyophilized, or the liquid pharmaceutical preparation of the present invention is prepared, lyophilized and stored / stored, followed by lyophilization and / Or by replenishing or replacing components removed or modified by storage / storage, liquid pharmaceutical preparations according to the present invention may be prepared.
  • only the components excluded from the components that can be removed or modified by lyophilization and / or storage / storage in the liquid pharmaceutical preparation of the present invention are lyophilized, or only the components are lyophilized and stored / stored , The above-mentioned excluded components may be added to prepare a liquid pharmaceutical preparation according to the present invention.
  • the present invention provides a method of treating a disease treatable with anti-TNF ⁇ , comprising subcutaneously administering to a subject a pharmaceutical composition containing an anti-TNF ⁇ antibody or antigen-binding fragment thereof.
  • the antibody may comprise one or more selected from the group consisting of infliximap, adalimumab, sertolium mappalol, golimumap, and biosimilars thereof.
  • the antibody may comprise an infliximap.
  • the antibody may comprise a chimeric human-mouse IgG monoclonal antibody.
  • the antibody or antigen-binding fragment thereof comprises a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 1, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 2, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: A light chain variable region comprising a light chain variable region; And a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 5, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 6.
  • the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7; And a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 8.
  • the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 9; And a heavy chain comprising the amino acid sequence of SEQ ID NO: 10.
  • the concentration of the antibody or antigen-binding fragment thereof may be 10 to 200 mg / mL.
  • the present invention also provides a kit comprising (A) an anti-TNFa antibody or antigen-binding fragment thereof; (B) a surfactant; (C) a sugar or derivative thereof; (D) a method of treating a disease treatable with anti-TNF ⁇ , comprising subcutaneously administering to the subject a composition comprising a buffer.
  • the surfactant may comprise polysorbate, poloxamer, or mixtures thereof.
  • the surfactant may comprise polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or a mixture of two or more thereof.
  • the surfactant may comprise polysorbate 80.
  • the concentration of (B) surfactant may be 0.02 to 0.1% (w / v).
  • the sugar (C) sugar comprises a monosaccharide, a disaccharide, an oligosaccharide, a polysaccharide or a mixture of two or more thereof, and the sugar derivative may comprise a sugar alcohol, a saccharic acid or a mixture thereof.
  • the sugar or derivative thereof may comprise sorbitol, mannitol, trehalose, sucrose or a mixture of two or more thereof.
  • the concentration of (C) sugar or derivative thereof may be 1-10% (w / v).
  • the buffer may comprise acetate or histidine.
  • the content of (D) buffer may be from 1 to 50 mM.
  • the pH of the composition may be between 4.0 and 5.5.
  • the composition may not contain aspartic acid, lysine, arginine or mixtures thereof.
  • the composition may not include NaCl, KCl, NaF, KBr, NaBr, Na 2 SO 4, NaSCN, K 2 SO 4 or mixtures thereof.
  • the composition may not contain a chelating agent.
  • the composition may not contain a preservative.
  • the composition may further comprise an aqueous carrier, an antioxidant, or a mixture of two or more thereof.
  • the composition has a viscosity of 0.5 cp to 10.0 cp measured after one month at 40 ° C ⁇ 2 ° C, or a viscosity of 0.5 cp to 5.0 cp measured after 6 months at 5 ° C ⁇ 3 ° C Lt; / RTI &gt;
  • the composition comprises (A) a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 1, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 2, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3 A light chain variable region comprising; And a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 5, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 6, Binding fragment; (B) a surfactant; (C) a sugar or derivative thereof; And (D) a buffer comprising acetate or histidine.
  • the composition comprises (A) a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 1, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 2, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3 A light chain variable region comprising; And a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 5, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 6, Binding fragments 90 to 180 mg / ml; (B) 0.02 to 0.1% (w / v) of a surfactant; (C) 1 to 10% (w / v) of a sugar or derivative thereof; And (D) 1 to 50 mM of a buffer comprising acetate or histidine.
  • a light chain variable region comprising
  • a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence of S
  • the composition can be administered subcutaneously.
  • the composition may not undergo a reconstitution step, dilution step or both before use.
  • the stable composition may be filled in a pre-filled syringe prior to use.
  • the composition may be included in an auto-injector prior to use.
  • the disease treatable with the anti-TNFa antibody is selected from the group consisting of rheumatoid arthritis, ulcerative colitis, Crohn's disease, scleroderma, psoriatic arthritis, ankylosing spondylitis, pediatric idiopathic arthritis, neonatal hemolytic disease, Ovarian cancer, gastric cancer, head and neck cancer, osteoporosis, paroxysmal nocturnal hemoglobinuria, invasive candidiasis infection, breast cancer, melanoma, chronic lymphocytic leukemia, chronic lymphocytic leukemia, Acute myelogenous leukemia, renal cell carcinoma, colon cancer, asthma, nasopharyngeal cancer, hemorrhagic shock, staphylococcal infections and follicular lymphoma.
  • the disease treatable with an anti-TNFa antibody may be a disease treatable by infliximab intravenous administration.
  • the disease treatable with the anti-TNF [alpha] antibody may be rheumatoid arthritis, ulcerative colitis, Crohn's disease, plaque psoriasis, psoriatic arthritis or ankylosing spondylitis treatable by intravenous infliximab.
  • the subject to be treated with anti-TNF ⁇ antibody is a patient who has insufficient response to disease-modifying anti-rheumatic drugs (DMARDs), including methotrexate.
  • DMARDs disease-modifying anti-rheumatic drugs
  • the anti-TNFa antibody administered subject is a patient who has not previously been treated with methotrexate and other DMARDs.
  • the subject to be treated with an anti-TNF ⁇ antibody is a patient who exhibits elevated serologic indicators associated with severe facial symptoms and inflammation, which do not show adequate response to universal therapy.
  • the subject to be administered an anti-TNF ⁇ antibody is a patient who does not respond to systemic therapy, which is methotrexate, cyclosporin or psoralen ultraviolet A therapy (PUVA), is contraindicated, or has intolerance.
  • systemic therapy which is methotrexate, cyclosporin or psoralen ultraviolet A therapy (PUVA)
  • PUVA psoralen ultraviolet A therapy
  • the subject to be administered an anti-TNF ⁇ antibody does not respond adequately to the treatment of a corticosteroid agent, 6-mercaptopurine, azathioprine or an immunosuppressive agent, is not tolerated, .
  • the subject to be treated with an anti-TNF ⁇ antibody is a patient who does not respond to a universal treatment, including antibiotics, excretion or immunosuppressive therapy.
  • the anti-TNFa antibody or binding fragment thereof may be administered in an amount of 60 to 300 mg. More specifically, it is possible to use a 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 290 or 300 mg.
  • the anti-TNFa antibody or binding fragment thereof may be administered in an amount of 90 to 180 mg. In another embodiment, the anti-TNF [alpha] antibody or binding fragment thereof may be administered in an amount of 120 to 240 mg. In another embodiment, the anti-TNF [alpha] antibody or binding fragment thereof may be administered in an amount of 120 to 240 mg.
  • the anti-TNF [alpha] antibody or binding fragment thereof may be administered 90 to 180 mg when the patient's body weight is less than 80 kg, or 190 to 270 mg if the patient's weight is 80 kg or more.
  • the anti-TNFa antibody or binding fragment thereof may be administered at intervals of 1 to 8 weeks. Specifically, it is preferable to administer the compound of the present invention at intervals of 1 week, 1.5 weeks, 2 weeks, 2.5 weeks, 3 weeks, 3.5 weeks, 4 weeks, 4.5 weeks, 5 weeks, 5.5 weeks, 6 weeks, 6.5 weeks, 7 weeks, 7.5 weeks, &Lt; / RTI &gt;
  • the anti-TNFa antibody or binding fragment thereof may be administered every 2 to 4 weeks apart.
  • the anti-TNF [alpha] antibody or antigen binding fragment thereof may be administered intravenously prior to the subcutaneous administration step of the anti-TNF [alpha] antibody or its binding fragment.
  • the anti-TNFa antibody or antigen-binding fragment thereof may be intravenously administered at 1 to 10 mg / kg before the subcutaneous administration step. Specifically, it may include intravenous administration of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 mg / kg.
  • the step of intravenously administering the anti-TNFa antibody or antigen-binding fragment thereof at 2 to 8 mg / kg may be included before the subcutaneous administration step.
  • the step of intravenously administering the anti-TNFa antibody or antigen-binding fragment thereof in an amount of 3 to 5 mg / kg may be included before the subcutaneous administration step.
  • the anti-TNFa antibody or antigen-binding fragment thereof may be intravenously administered at intervals of 1 to 8 weeks before the subcutaneous administration step.
  • the intravenous administration may be performed at intervals of 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 or 8 weeks.
  • the anti-TNFa antibody or antigen-binding fragment thereof may be intravenously administered at intervals of 2 to 4 weeks before the subcutaneous administration step.
  • the intravenous administration of the anti-TNFa antibody or antigen-binding fragment thereof prior to the subcutaneous administration step may include a step wherein the interval between the final intravenous administration and the initial subcutaneous administration is 1 to 8 weeks have. Specifically, they may be administered at intervals of 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 or 8 weeks.
  • the step of intravenously administering the anti-TNFa antibody or antigen-binding fragment thereof before the subcutaneous administration step wherein the interval between the last intravenous administration and the initial subcutaneous administration is 2 to 4 weeks .
  • Other biological or chemotherapeutic agents may be administered in combination with an anti-TNFa antibody of the invention or an antigen-binding fragment thereof.
  • Administration is administered simultaneously, prior to, or after administration of the anti-TNF [alpha] antibody or antigen binding fragment thereof.
  • the biologic agent to be coadministered is selected from the group consisting of Etanercept, Infliximab, Adalimumab, Sertolizumab pegol, Golimumab, .
  • the chemotherapeutic agent administered concomitant may comprise a disease-modifying anti-rheumatic drug (DMARD).
  • DMARD disease-modifying anti-rheumatic drug
  • the coadministered chemotherapeutic agent may include Methotrexate, Leflunomide, Sulfasalazine, Hydroxychloroquine, or a combination thereof.
  • the invention also relates to a composition comprising an anti-TNF [alpha] antibody or a binding fragment thereof; And a container for containing the composition in a sealed state.
  • composition containing the anti-TNFa antibody or a binding fragment thereof is as described above.
  • the container can be formed from materials such as glass, polymer (plastic), metal, and the like, but is not limited thereto.
  • the container is a bottle, vial, cartridge, syringe (pre-field syringe, automatic syringe), or tube, but is not limited thereto.
  • the container can be a glass or polymer vial, or a glass or polymer free-field syringe.
  • the product commercialized as the vial, the cartridge, the free-field syringe, the automatic syringe, etc. may be used as is, or separately prepared in consideration of the physical properties, administration site and dosage of the composition containing the anti-TNF ⁇ antibody or a binding fragment thereof One product is available.
  • the inside of the container may not be coated with silicone oil. Stability may be impaired if silicone oil is coated.
  • the container may be a single-dose or multi-dose container.
  • the product may further comprise instructions for using the composition containing the anti-TNFa antibody or a binding fragment thereof, a storage method, or both.
  • Such methods of use include the treatment of diseases for which the activity of TNFa is detrimental and may include the route of administration, dosage and timing of administration.
  • the product may include other tools, such as needles, syringes and the like, that are necessary from a commercial and user perspective.
  • Example 1 Assessment of safety and therapeutic efficacy in the subcutaneous administration of infliximab in patients with rheumatoid arthritis (RA)
  • Infliximab clinical trial was conducted in patients with active rheumatoid arthritis who did not respond to methotrexate (MTX) monotherapy for more than 3 months, in combination with MTX and folate, and infliximab (Infliximab SC) for subcutaneous administration
  • MTX methotrexate
  • Infliximab SC infliximab
  • Part 1 is designed to determine the optimal dose of Infliximab SC and is based on an infliximab equivalent to 3 mg / kg Infliximab IV over the first 30 weeks through a steady state concentration-time curve (AUC ⁇ ) between 22 and 30 weeks The optimal capacity of SC was confirmed.
  • the trial period was up to 65 weeks, from screening (up to 3 weeks) to ending the trial.
  • Part 2 is designed to demonstrate the non-inferiority of effectiveness between Infliximab SC and Infliximab IV.
  • Clinical responses to baseline changes in disease activity scores (DAS28; C-Reactive Protein, CRP) from 28 to 22 joints were used to assess efficacy Will prove that inflex map SC is not inferior to inflex map IV.
  • DAS28 disease activity scores
  • CRP C-Reactive Protein, CRP
  • B type C and human immunodeficiency virus (HIV-1, HIV-2) infections, urine and serum pregnancy tests for pregnant women, rheumatic factors, anti-cyclic citrullinated peptides, 12-lead ECG, clinical laboratory tests, and so on.
  • Interferon gamma secretion test (IGRA) and chest X-ray were also performed to exclude patients with tuberculosis.
  • Infliximab IV was administered to all patients enrolled in clinical trials at doses of 0 week and 2 weeks. Folic acid was administered concomitantly with MTX, the study drug, to minimize or prevent adverse events associated with MTX adverse events, and MTX doses should be maintained from the beginning of the trial to the end of the trial.
  • the patient could receive the following pre-dose (but not limited to) at the discretion of the tester at 30 to 60 minutes prior to the start of the test drug in order to prevent hypersensitivity to the test drug at the discretion of the tester : Antihistamine [2 to 4 mg of chlorpenilamine or equivalent], hydrocortisone, paracetamol and / or sedating antihistamines [in an amount of 10 mg cetirizine, etc.]).
  • Cohort Number Dose Drugs for Clinical Trials Method of administration Number of patients Cohort 1 3 mg / kg Infliximab IV 100 mg / vial 2 hour IV infusion 13 Cohort 2 90 mg Infliximab SC 90 mg / PFS Single SC injection 11 Cohort 3 120 mg Infliximab SC 120 mg / PFS Single SC injection 12 Cohort 4 180 mg Infliximab SC 90 mg / PFS 2 SC injections 12
  • an additional seven doses of infliximab IV were given at 6 weeks and then every 8 weeks (14, 22, 30, 38, 46, and 54 weeks).
  • the first infliximab SC was administered at 6 weeks, and the additional infliximab SC was administered every 2 weeks until 54 weeks.
  • the first dose assigned to all patients in cohorts 2, 3, and 4 was adjusted to the optimal dose after dose verification. Additional SC injections with optimal doses were then administered up to 54 weeks.
  • Infliximab SC is injected by a medical practitioner at each laboratory visit (6, 8, 10, 14, 22, 24, 26, 28, 30, 38, 46 and 54 weeks) , 32, 34, 36, 40, 42, 44, 48, 50, 52 weeks), the patient was able to self-inject infliximab SC if the tester determined appropriate after appropriate injection technique training.
  • Clinical trial end visits were conducted at the end of the maintenance phase or at the end of the 8 week period following the last dose when the patient was withdrawn. Every effort was made to complete the evaluation of all clinical trials at the eighth week after the patient received the last dose.
  • Part 2 was initiated based on a review of the independent data safety monitoring committee on PK modeling report data, including PK, validity, PD and safety data over the first 30 weeks identified in Part 1.
  • Part 2 consisted of three clinical trials, including screening, a double-blind period of up to 30 weeks followed by a 24-week open-label period, and termination of the trial. Screening was conducted between days -42 and 0 before the first administration of the test drug, and the eligibility of the patient was evaluated.
  • B type C and human immunodeficiency virus (HIV-1, HIV-2) infections, urine and serum pregnancy tests for pregnant women, rheumatic factors, anti-cyclic citrullinated peptides, 12-lead ECG, clinical laboratory tests, and so on.
  • Interferon gamma secretion test (IGRA) and chest X-ray were also performed to exclude patients with tuberculosis.
  • Infliximab IV was administered to all patients enrolled in clinical trials at doses of 0 week and 2 weeks. Folic acid was administered concomitantly with MTX, the study drug, to minimize or prevent adverse events associated with MTX adverse events, and MTX doses should be maintained from the beginning of the trial to the end of the trial.
  • the patient may receive the following pre-dose (but not limited to) antihistamine at the discretion of the tester 30 to 60 minutes prior to the start of the test drug to prevent hypersensitivity reactions to the test drug Hydrocortisone, paracetamol and / or sedating antihistamines [in an amount of about 10 mg cetirizine, etc.]).
  • Group number Dose Drugs for Clinical Trials Method of administration Number of patients Group 1 3 mg / kg Infliximab IV 100 mg / vial 2 hour IV infusion At least 109 Group 2 120 mg Infliximab SC 120 mg / PFS Single SC injection At least 109
  • infliximab IV For patients assigned to group 1, an additional three doses of infliximab IV were given every 6 weeks and then every 8 weeks (14 and 22 weeks) up to 22 weeks, and placebo SC every 2 weeks until 6 weeks and then 28 weeks . Infixagram IV was later converted to Infliximab SC (PFS) in 30 weeks. Infliximab SC (PFS) is then administered up to 54 weeks. For patients assigned to group 2, the first infliximab SC (PFS) was given every 6 weeks and every 2 weeks thereafter, lasting up to 54 weeks, and placebo IV was given at 6, 14, and 22 weeks.
  • PFS Infliximab SC
  • Infliximab SC placebo SC for double-blind period
  • Infliximab SC placebo SC for double-blind period
  • the patient may self-inject infliximab SC (placebo SC for a double-blind period) if the tester decides it is appropriate after appropriate injection technique training.
  • infliximab SC is self-administered as an auto-injector (AI) every two weeks from week 46.
  • AI auto-injector
  • Self-medication pre- and postdiagnosis questionnaires, self-medication diagnosis checklists, and potential risk checklist assessments are performed to assess the usability of infliximab SC (AI).
  • Part 2 of the Clinical Assessment, Blood Collection, and Clinical Trial visits of Part 2 is done in the same manner and is collected and performed at the time specified in the evaluation schedule.
  • Safety assessments are secondary assessment variables in Part 1, which include immunogenicity, hypersensitivity monitoring (including monitoring of delayed hypersensitivity reactions), vital signs measurements (including blood pressure, heart rate and respiratory rate, body temperature), body weight, interferon gamma secretion test, chest X 12-Induced ECG, anomalous cases (including serious abnormal cases), special attention abnormal reactions (infectious diseases, infectious diseases, Clinical laboratory analysis, Pregnancy test, Pre- and co-medication, 10-cm visual analogue scale (MRI) (Visual Analogue Scale, VAS).
  • MRI Visual Analogue Scale
  • the cumulative safety data in this study included adverse events (and serious adverse events) that did not correlate with the clinical drug until the end of the trial, and included an outbreak of adverse events occurring during the maintenance phase (6 to 54 weeks)
  • the overall summary is shown in Table 3.
  • 109 (69.8%) of these cases occurred in 33 (68.8%) of patients, and 9 (69.2%) in the IV cohort (cohort 1) and 24 (68.6%) in the total SC cohort ), And showed a similar ratio to the IV cohort in the entire SC cohort.
  • the intensity of the abnormal cases after the most treatment was classified as grade 1 or 2, and abnormal cases occurred in 23 (47.9%) of the cases after all treatments were regarded as related to this system.
  • One patient in Cohort 2 received Infliximab IV at doses of 0, 2, and 2 weeks of dosing, and received two doses of Infliximab SC at 6 and 8 weeks. Medication-related reactions occurred at 6 and 8 weeks, and at 6 weeks and at the end of the study visit (10 weeks after the 8-week visit), antibody and neutralizing antibodies against the drug were identified.
  • One patient in Cohort 1 had a dose response-related response at 38 weeks, and at 30 and 38 weeks and at the end of the trial (10 weeks after the 38-week visit), the positive and negative antibodies to the drug were confirmed .
  • the proportion of patients positive for the drug (ADA) against the drug was low in the SC cohort, and at week 54 most patients were negative for the drug (ADA).
  • the positive rate of antibody (ADA) to drug was low as the SC dose increased.
  • the number of patients positive for the drug (ADA) at 54 weeks was 9 (69.2%), 4 (36.4%), 2 (16.7%) and 2 (16.7%) in the cohort 1 to 4, respectively ).
  • ADA antibody to drug
  • NAb neutralizing antibody
  • VAS visual analog scale
  • the range of the visual analog scale (VAS) is 0 to 100 mm, and higher scores indicate more severe pain.
  • a slightly higher level of localized pain was observed in the SC cohort (cohort 2, 3, 4) than in the IV cohort (cohort 1) at the first SC administration (6 weeks).
  • SC administration localized pain was gradually reduced and a lower level of pain was reported in the SC cohort (cohort 2, 3, 4) than in the IV cohort (cohort 1).
  • cohort 4 which received twice the SC 90 mg formulation, showed a higher incidence of pain than the other two SC cohorts, but a lower level of pain than the IV cohort (cohort 1) was reported (Table 5) .
  • DAS28 C reactive protein (CRP), erythrocyte sedimentation rate (ESR)
  • CRP reactive protein
  • ESR erythrocyte sedimentation rate
  • Example 2 Modeling of subcutaneous administration of infliximab in patients with rheumatoid arthritis (RA)
  • the pharmacokinetic-pharmacodynamic (PK-PD) model for infliximab subcutaneous (SC) is a quantitative pharmacokinetic (PK) model for simulating the infliximab SC efficacy and safety as well as simulating the PK of future doses and regimens
  • PK-PD quantitative pharmacokinetic-pharmacodynamic
  • the pharmacokinetic-pharmacodynamic model includes infliximab intravenous data and Crohn's disease (CD) patients in healthy subjects, Ankylosing Spondylitis (AS), rheumatoid arthritis (RA) and Crohn's disease (Clinicaltrials.gov identifiers NCT01220518, NCT01217086, NCT02096861) of arthritis (RA) patients and healthy volunteers.
  • the PK-PD model constructed on the basis of the above data can be used to simulate the results of subcutaneous administration to infliximab indications (rheumatoid arthritis, ulcerative colitis, Crohn's disease, scleroderma, psoriatic arthritis, or ankylosing spondylitis) patients have.
  • PK-PD modeling analysis was performed using a non-linear mixed-effect modeling approach. Data analysis began with a one-compartment model containing proportional elimination of the proportional-error model, and the final model was performed with a two-compartment model with linear elimination from the central compartment. All models for pharmacokinetics were parameterized in terms of clearance (CL) and distribution volumes.
  • SC subcutaneous
  • RA rheumatoid arthritis
  • the exposure pharmacokinetic parameters (AUC ⁇ , C trough and C max ) for the infliximab SC dosage regimen were simulated by dividing by 10 kg for the 50-130 kg body weight range and the lowest serum concentration of infliximab SC exposure by body weight (C trough ), and the concentration-time curve subscale (AUC ⁇ ) estimates correlated with drug doses (Table 12).
  • Example 3 Safety and efficacy of subcutaneous administration of infliximab in patients with Crohn's disease (CD) or ulcerative colitis (UC)
  • This Infliximab trial is an open, randomized, multicenter, parallel group, phase 1 trial designed to assess pharmacokinetics, efficacy and safety of Infliximab SC and Infliximab IV in patients with active Crohn's disease or active ulcerative colitis until 54 weeks, This clinical trial consists of two parts.
  • Part 1 was designed to determine the optimal dose of Infliximab SC in patients with Crohn's disease (CD) and was assessed using a steady-state concentration-time curve (AUC ⁇ ) between 22 and 30 weeks at 5 mg / kg infleximap IV. &lt; tb &gt;&lt; TABLE &gt; For Part 1, the duration of the trial is a maximum of 65 weeks, including screening (up to 3 weeks) to the end of the trial.
  • AUC ⁇ steady-state concentration-time curve
  • Part 2 is designed to confirm that Infliximab SC is not pharmacologically inferior to Infliximab SC in patients with Crohn's disease (CD) or ulcerative colitis (UC), and is demonstrated through pre-dose concentrations (C troughs ) at 22 weeks will be.
  • the infliximab SC optimal dose and interval of administration corresponding to 5 mg / kg Infliximab IV in Part 2 was determined based on the pharmacokinetics and efficacy, pharmacodynamics, and safety data for the first 30 weeks of Part 1, Board, DSMB) as follows.
  • IGRA interferon gamma secretion
  • chest X-ray were also performed to exclude patients with tuberculosis.
  • Cohort Number Dose Drugs for Clinical Trials Method of administration Number of patients Cohort 1 5 mg / kg Infliximab IV 100 mg / vial 2 hour IV infusion 13 Cohort 2 120 mg Infliximab SC 120 mg / PFS Single SC injection 11 Cohort 3 180 mg Infliximab SC 90 mg / PFS 2 SC injections 12 Cohort 4 240 mg Infliximab SC 120 mg / PFS 2 SC injections 8
  • an additional 7 doses of Infliximab IV are given every 6 weeks and then every 8 weeks (14, 22, 30, 38, 46 and 54 weeks).
  • the first infliximab SC was given at 6 weeks, and the additional infliximab SC was given every 2 weeks up to 54 weeks.
  • the initial dose assigned to all patients in cohorts 2, 3, and 4 is adjusted to the optimal dose after dosing. Additional SC injections with optimal doses are then administered up to 54 weeks.
  • Infliximab SC is injected by a medical practitioner at each laboratory visit (6, 8, 10, 14, 22, 24, 26, 28, 30, 38, 46 and 54 weeks) , 32, 34, 36, 40, 42, 44, 48, 50, 52 weeks), the patient can self-inject infliximab SC if the tester decides it is appropriate after appropriate injection technique training.
  • the patient visits the laboratory at predefined time intervals for clinical evaluation and blood collection. At each visit, the patient is asked about adverse events (AEs) and concomitant medications and is monitored for clinical signs and symptoms of TB. Evaluation of primary pharmacokinetic parameters was carried out during the maintenance phase between 22 and 30 weeks. The evaluation of secondary pharmacokinetic parameters was performed during the period of administration up to 54 weeks. The blood sample for analysis, efficacy, PD and safety evaluation were performed at the time .
  • AEs adverse events
  • concomitant medications concomitant medications
  • the end-of-study visit is conducted 8 weeks after the end of the maintenance phase. However, if the patient is to discontinue the mid-course clinical trial, it should be administered 8 weeks after the last dose. For patients who have been dropped out, all clinical trial procedures are carried out on the next day after drop-off or drop-out and all efforts are made to complete the evaluation of all clinical trials at eight weeks after the patient has received the last dose.
  • Part 2 will be based on a review of the Independent Data Safety Monitoring Committee on PK modeling report data, including PK, validity, PD and safety data for the first 30 weeks identified in Part 1.
  • Patients may not be enrolled in Part 2 of the clinical trial if one of the following criteria is met:
  • Part 2 will consist of three clinical trials: screening, period of administration, and termination of the study. Screening will be conducted between days -42 and 0 before the first dose of the test drug and will evaluate the eligibility of the patient for the study. Urinary and serologic tests for pregnant women, Colonoscopy (Crohn's disease), rectal S-phase colonoscopy (patients with ulcerative colitis), Inflammatory Bowel Disease (IBD) , CRP, 12-lead ECG, clinical laboratory tests, and so on. In addition, interferon gamma secretion (IGRA) and chest x-ray examination will be performed to exclude patients with tuberculosis.
  • IGRA interferon gamma secretion
  • chest x-ray examination will be performed to exclude patients with tuberculosis.
  • Patients who meet all of the criteria for selection and who do not meet any of the exclusion criteria are enrolled in the study, and all registered patients receive Infliximab IV at a dose of 0, 2, or 2 doses Lt; / RTI &gt; Patients may receive (but are not limited to) the following pre-dose (s) selected at the discretion of the tester at 30-60 minutes prior to the start of the test drug to prevent hypersensitivity reactions to the test drug at the discretion of the tester
  • Antihistamines [in an amount of 2 to 4 mg chlorpenilamine and the like], hydrocortisone, paracetamol and / or sedating antihistamines [such as cetirizine 10 mg]).
  • Group number Dose Drugs for Clinical Trials Method of administration Number of patients Group 1 5 mg / kg Infliximab IV 100 mg / vial 2 hour IV infusion At least 65 people Group 2 120 mg ( ⁇ 80 kg) Infliximab SC 120 mg / PFS Single SC injection At least 65 people 240 mg ( ⁇ 80 kg) Infliximab SC 120 mg / PFS 2 SC injections
  • infliximab SC is based on 6 weeks of body weight and is dosed every 2 weeks from 6 weeks to 54 weeks. Capacity increase will be allowed after 30 weeks according to the tester's judgment.
  • Infliximab SC is injected by a health care provider at each laboratory visit (6, 14, 22, 24, 26, 28, 30, 38, 46, and 54 weeks) The patient can self-inject Infliximab SC.
  • Clinical trial end visits are conducted two weeks after the end of the maintenance phase. However, if the patient is to stop the clinical trial after a moderate SC administration, it should be administered two weeks after the last dose. If the patient is to discontinue the clinical trial after a moderate IV dose, it should be administered 8 weeks after the last dose. For patients who have been dropped out, all clinical trial procedures should be carried out on the day following drop-off or drop-out, and all efforts shall be made to complete the evaluation of all clinical trials at the time point after the patient has received the last dose.
  • Part 2 of the Clinical Assessment, Blood Collection and Clinical Trial visits of Part 2 will be done in the same manner and will be collected and performed at the time specified in the evaluation schedule.
  • the safety assessment is a secondary endpoint of Part 1 and includes immunogenicity, hypersensitivity monitoring (including delayed hypersensitivity monitoring), vital signs measurement (including blood pressure, heart rate and respiration rate, body temperature), body weight, interferon gamma secretion test, chest X- 12-Induced ECG, abnormal cases (including serious abnormal cases), special cases of abnormal cases (infectious diseases, infectious diseases, Clinical laboratory analysis, pregnancy test, previous and concurrent medication, 100 mm visual analogue scale (MRI), response time / hypersensitivity / anaphylaxis response, delayed hypersensitivity reaction, injection site reaction, infection and malignancy) Visual Analogue Scale (VAS).
  • MRI visual analogue scale
  • VAS Visual Analogue Scale
  • the cumulative safety data for this study was included for up to 30 weeks and an overall summary of the abnormal cases that occurred after the treatment during the maintenance phase (6 to 30 weeks) is shown in Table 15. Overall, 70 cases of abnormal cases occurred in 28 patients (63.6%), 8 cases (61.5%) in the IV cohort (cohort 1), 20 cases (64.5%) in the total SC cohort And a similar rate was observed in both groups. In addition, the intensity of the abnormal cases after most of the treatments appeared to be 1st or 2nd grade, and 9 cases (20.5%) of the abnormal cases after all treatments were regarded as related to this case.
  • Adverse events following treatment of infection occurred in 2 (15.4%) of the IV cohort (cohort 1) and 7 (22.6%) of the SC cohort (cohort 2-4).
  • the proportion of patients positive for the drug (ADA) was lower in the SC cohort, and at 30 weeks most patients were negative for the drug (ADA).
  • the number of patients positive for the drug (ADA) at 30 weeks was 8 (61.5%), 0 (0.0%), 3 (25.0%) and 1 (12.5%) in the cohort 1 to 4, respectively ).
  • ADA antibody to drug
  • NAb neutralizing antibody
  • Percent visits were calculated using the number of randomly assigned patients as the denominator.
  • VAS visual analog scale
  • VAS visual analogue scale
  • the CDAI (Crohn's disease activity index) scores of 2, 6, 14, 22 and 30 weeks were compared with the baseline as secondary efficacy variables. As a result, it was confirmed that the actual value decreased with time in each cohort.
  • the percentage of patients who responded to the CDAI-70 response criteria was similar between the treatment groups (Table 19).
  • the percentage of patients who responded to the CDAI-100 response criteria was also similar between the treatment groups (Table 20).
  • Example 2 The procedure of Example 2 was repeated.
  • Reference therapy is a 2-hour intravenous infusion of 5 mg / kg infliximab at 8-week intervals (maintenance therapy).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Dermatology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/KR2018/009998 2017-08-30 2018-08-29 TNFα 관련 질환을 치료하는 방법 WO2019045452A1 (ko)

Priority Applications (19)

Application Number Priority Date Filing Date Title
BR112020003951-9A BR112020003951A2 (pt) 2017-08-30 2018-08-29 métodos para tratar doenças relacionadas a tnf
CR20200095A CR20200095A (es) 2017-08-30 2018-08-29 MÉTODOS PARA EL TRATAMIENTO DE ENFERMEDADES RELACIONADAS CON TNFa
JOP/2020/0046A JOP20200046A1 (ar) 2017-08-30 2018-08-29 طرق لعلاج أمراض مرتبطة بـtnf?
CN201880055961.9A CN111094342A (zh) 2017-08-30 2018-08-29 用于治疗TNFα相关疾病的方法
MX2020002278A MX2020002278A (es) 2017-08-30 2018-08-29 Metodos para el tratamiento de enfermedades relacionadas con tnfa.
SG11202001739YA SG11202001739YA (en) 2017-08-30 2018-08-29 METHOD FOR TREATING TNFα-RELATED DISEASE
AU2018326037A AU2018326037A1 (en) 2017-08-30 2018-08-29 Method for treating TNFα-related disease
CU2020000015A CU20200015A7 (es) 2017-08-30 2018-08-29 Composición farmacéutica y kit que comprenden anticuerpos anti-tnf alpha
EA202090544A EA202090544A1 (ru) 2017-08-30 2018-08-29 Способ лечения заболевания, связанного с tnf-
JP2020512018A JP2020532520A (ja) 2017-08-30 2018-08-29 ＴＮＦα関連疾患の治療方法
US16/643,377 US20210371510A1 (en) 2017-08-30 2018-08-29 Methods for Treating TNFa-Related Diseases
EP18852415.1A EP3677596A4 (en) 2017-08-30 2018-08-29 METHODS OF TREATMENT FOR TNF RELATED DISEASE
CA3074168A CA3074168A1 (en) 2017-08-30 2018-08-29 Method for treating tnf.alpha.-related diseases
CONC2020/0002117A CO2020002117A2 (es) 2017-08-30 2020-02-27 Métodos para el tratamiento de enfermedades relacionadas con tnfα
PH12020550066A PH12020550066A1 (en) 2017-08-30 2020-02-27 METHOD FOR TREATING TNFa-RELATED DISEASE
DO2020000049A DOP2020000049A (es) 2017-08-30 2020-02-28 MÉTODOS PARA EL TRATAMIENTO DE ENFERMEDADES RELACIONADAS CON TNFa
IL272977A IL272977A (en) 2017-08-30 2020-02-28 A method for treating a disease related to TNFα
ZA2020/01927A ZA202001927B (en) 2017-08-30 2020-03-24 Method for treating tnf alpha-related diseases
JP2023196788A JP2024023347A (ja) 2017-08-30 2023-11-20 ＴＮＦα関連疾患の治療方法

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
KR10-2017-0110426 2017-08-30
KR20170110426 2017-08-30
KR10-2017-0144521 2017-11-01
KR20170144521 2017-11-01
KR1020180017449A KR20190024572A (ko) 2017-08-30 2018-02-13 TNFα 관련 질환을 치료하기 위한 피하 투여 요법
KR10-2018-0017449 2018-02-13

Publications (1)

Publication Number Publication Date
WO2019045452A1 true WO2019045452A1 (ko) 2019-03-07

Family

ID=65801706

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2018/009998 WO2019045452A1 (ko) 2017-08-30 2018-08-29 TNFα 관련 질환을 치료하는 방법

Country Status (25)

Country Link
US (1) US20210371510A1 (ja)
EP (1) EP3677596A4 (ja)
JP (2) JP2020532520A (ja)
KR (2) KR20190024572A (ja)
CN (1) CN111094342A (ja)
AU (1) AU2018326037A1 (ja)
BR (1) BR112020003951A2 (ja)
CA (1) CA3074168A1 (ja)
CL (1) CL2020000479A1 (ja)
CO (1) CO2020002117A2 (ja)
CR (1) CR20200095A (ja)
CU (1) CU20200015A7 (ja)
DO (1) DOP2020000049A (ja)
EA (1) EA202090544A1 (ja)
EC (1) ECSP20014569A (ja)
GE (1) GEP20237521B (ja)
IL (1) IL272977A (ja)
JO (1) JOP20200046A1 (ja)
MA (1) MA50046A (ja)
MX (1) MX2020002278A (ja)
PH (1) PH12020550066A1 (ja)
SG (1) SG11202001739YA (ja)
TW (1) TW201919697A (ja)
WO (1) WO2019045452A1 (ja)
ZA (1) ZA202001927B (ja)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AR118191A1 (es) * 2019-02-28 2021-09-22 Celltrion Inc MÉTODOS PARA EL TRATAMIENTO DE ENFERMEDADES RELACIONADAS CON TNFa

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4861335A (en) 1985-07-26 1989-08-29 Duoject Medical Systems Inc. Syringe
US5085642A (en) 1989-07-17 1992-02-04 Survival Technology, Inc. Conveniently carried frequent use autoinjector
US5681291A (en) 1992-11-19 1997-10-28 Tebro S.A. Disposable auto-injector for prefilled syringes
US6284471B1 (en) 1991-03-18 2001-09-04 New York University Medical Center Anti-TNFa antibodies and assays employing anti-TNFa antibodies
US6331174B1 (en) 1994-10-27 2001-12-18 Schott Glaswerke Prefilled, low particle, sterile disposable syringe for injecting preparations and procedure for manufacture
KR20100075698A (ko) * 2001-06-08 2010-07-02 애보트 바이오테크놀로지 리미티드 항－ＴＮＦα 항체를 포함하는 약제학적 조성물
KR20100106631A (ko) * 2002-04-26 2010-10-01 애보트 바이오테크놀로지 리미티드 Ｔｎｆ알파 항체와 기타 약물의 용도
KR20130108477A (ko) * 2004-04-09 2013-10-02 애브비 바이오테크놀로지 리미티드 ＴＮＦα-관련 질환을 치료하기 위한 다중-가변 투여 요법
KR20130135266A (ko) * 2010-11-11 2013-12-10 애브비 바이오테크놀로지 리미티드 개선된 고농도 항－ＴＮＦα 항체 액체 제형
KR20140054085A (ko) * 2011-07-19 2014-05-08 글락소 그룹 리미티드 증가된 fcrn 결합을 갖는 tnf-알파 항원-결합 단백질
KR20150110659A (ko) * 2013-01-24 2015-10-02 글락소스미스클라인 인털렉츄얼 프로퍼티 디벨로프먼트 리미티드 Tnf-알파 항원-결합 단백질
KR20170081814A (ko) 2016-01-05 2017-07-13 이경록 헤어 브러시

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050249735A1 (en) * 2000-08-07 2005-11-10 Centocor, Inc. Methods of treating ankylosing spondylitis using anti-TNF antibodies and peptides of human tumor necrosis factor
US20040126372A1 (en) * 2002-07-19 2004-07-01 Abbott Biotechnology Ltd. Treatment of TNFalpha related disorders
SG175188A1 (en) * 2009-05-04 2011-11-28 Abbott Biotech Ltd Stable high protein concentration formulations of human anti-tnf-alpha-antibodies
EP3078675A1 (en) * 2015-04-10 2016-10-12 Ares Trading S.A. Induction dosing regimen for the treatment of tnf alpha mediated disorders
CA3013336A1 (en) * 2016-02-03 2017-08-10 Oncobiologics, Inc. Buffer formulations for enhanced antibody stability
MX2018015960A (es) * 2016-06-30 2019-03-21 Celltrion Inc Formulacion farmaceutica liquida estable.

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4861335A (en) 1985-07-26 1989-08-29 Duoject Medical Systems Inc. Syringe
US5085642A (en) 1989-07-17 1992-02-04 Survival Technology, Inc. Conveniently carried frequent use autoinjector
US6284471B1 (en) 1991-03-18 2001-09-04 New York University Medical Center Anti-TNFa antibodies and assays employing anti-TNFa antibodies
US5681291A (en) 1992-11-19 1997-10-28 Tebro S.A. Disposable auto-injector for prefilled syringes
US6331174B1 (en) 1994-10-27 2001-12-18 Schott Glaswerke Prefilled, low particle, sterile disposable syringe for injecting preparations and procedure for manufacture
KR20100075698A (ko) * 2001-06-08 2010-07-02 애보트 바이오테크놀로지 리미티드 항－ＴＮＦα 항체를 포함하는 약제학적 조성물
KR20100106631A (ko) * 2002-04-26 2010-10-01 애보트 바이오테크놀로지 리미티드 Ｔｎｆ알파 항체와 기타 약물의 용도
KR20130108477A (ko) * 2004-04-09 2013-10-02 애브비 바이오테크놀로지 리미티드 ＴＮＦα-관련 질환을 치료하기 위한 다중-가변 투여 요법
KR20130135266A (ko) * 2010-11-11 2013-12-10 애브비 바이오테크놀로지 리미티드 개선된 고농도 항－ＴＮＦα 항체 액체 제형
KR20140054085A (ko) * 2011-07-19 2014-05-08 글락소 그룹 리미티드 증가된 fcrn 결합을 갖는 tnf-알파 항원-결합 단백질
KR20150110659A (ko) * 2013-01-24 2015-10-02 글락소스미스클라인 인털렉츄얼 프로퍼티 디벨로프먼트 리미티드 Tnf-알파 항원-결합 단백질
KR20170081814A (ko) 2016-01-05 2017-07-13 이경록 헤어 브러시

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DAVIS, J.M. ET AL., BIOCHEMISTRY, vol. 26, 1987, pages 1322 - 1326
JONES, E.Y. ET AL., NATURE, vol. 338, 1989, pages 225 - 228
PENNICA, D. ET AL., NATURE, vol. 312, 1984, pages 724 - 729
See also references of EP3677596A4

Also Published As

Publication number Publication date
IL272977A (en) 2020-04-30
MA50046A (fr) 2020-07-08
CO2020002117A2 (es) 2020-04-01
CR20200095A (es) 2020-05-10
TW201919697A (zh) 2019-06-01
KR20190024809A (ko) 2019-03-08
EA202090544A1 (ru) 2020-06-05
KR20190024572A (ko) 2019-03-08
CN111094342A (zh) 2020-05-01
GEP20237521B (en) 2023-07-25
JOP20200046A1 (ar) 2020-02-27
BR112020003951A2 (pt) 2020-09-08
CU20200015A7 (es) 2020-12-17
AU2018326037A1 (en) 2020-01-30
EP3677596A1 (en) 2020-07-08
ECSP20014569A (es) 2020-07-31
EP3677596A4 (en) 2021-07-28
US20210371510A1 (en) 2021-12-02
MX2020002278A (es) 2020-07-13
JP2020532520A (ja) 2020-11-12
JP2024023347A (ja) 2024-02-21
DOP2020000049A (es) 2020-03-15
CA3074168A1 (en) 2019-03-07
SG11202001739YA (en) 2020-03-30
PH12020550066A1 (en) 2021-02-15
ZA202001927B (en) 2021-08-25
CL2020000479A1 (es) 2020-10-02

Similar Documents

Publication Publication Date Title
US20200354453A1 (en) Stable formulations of anti-tigit antibodies alone and in combination with programmed death receptor 1 (pd-1) antibodies and methods of use thereof
WO2018004260A1 (ko) 안정한 액체 약제학적 제제
WO2013100704A1 (en) A site-specific glp-2 conjugate using an immunoglobulin fragment
IL207985A (en) Human antibodies Immunomodulatory monoclonal antibodies for the treatment of immunological failure
WO2018131893A1 (ko) 안정한 액체 제제
WO2021067820A1 (en) Formulation of antibody-drug conjugate
WO2016085289A1 (ko) B형 간염 바이러스의 pres1에 특이적으로 결합하는 항체 및 이의 용도
WO2013147559A1 (en) A liquid formulation of highly concentrated long-acting human growth hormone conjugate
WO2019045452A1 (ko) TNFα 관련 질환을 치료하는 방법
WO2021182874A1 (ko) 안정성이 증진된 액상 약제학적 조성물
WO2019045477A1 (ko) 비멘틴 유래 펩타이드에 특이적으로 결합하는 물질을 포함하는 피부질환 예방 및 치료용 조성물
WO2020004937A1 (ko) 항-bcma 항체-약물 접합체 및 그 용도
WO2021096278A1 (ko) 항체 의약품용 액상 조성물
WO2022015093A1 (ko) 사스-코로나바이러스 감염증을 예방 또는 치료하기 위한 투여 요법
WO2023059113A1 (en) Treatment of mast cell related disorders
US20060171940A1 (en) Antibody disulfide isomers, use thereof, and methods of analyzing same
WO2023191470A1 (ko) Api5 단백질에 특이적으로 결합하는 항체
KR20200105439A (ko) TNFα 관련 질환을 치료하는 방법
WO2018124851A1 (ko) L1cam 단백질에 특이적으로 결합하는 항체; 및 피리미딘 유사체 및/또는 플라틴계 항암제를 포함하는 암의 예방 또는 치료용 약학적 조성물
WO2023182657A1 (ko) 항-fetuin-b 항체 및 해당 항체를 유효 성분으로 포함하는 근육질환의 예방, 치료 또는 개선용 조성물
WO2023234611A1 (en) Viscosity-reducing excipient composition and low-viscosity highly concentrated protein formulation containing same
WO2020106116A9 (ko) 인플루엔자 바이러스 질환을 치료하기 위한 투여 요법
WO2023157989A1 (ko) 항체-약물 접합체
WO2023214778A1 (ko) 항-cd300c 항체 또는 이의 항원 결합 단편 및 그의 퇴행성 뇌 질환 예방 또는 치료용 용도
WO2022045857A2 (ko) 안정한 약제학적 제제

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18852415

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2018326037

Country of ref document: AU

Date of ref document: 20180829

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 3074168

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2020512018

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 272977

Country of ref document: IL

NENP Non-entry into the national phase

Ref country code: DE

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112020003951

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 15302

Country of ref document: GE

ENP Entry into the national phase

Ref document number: 2018852415

Country of ref document: EP

Effective date: 20200330

ENP Entry into the national phase

Ref document number: 112020003951

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20200227

WWE Wipo information: entry into national phase

Ref document number: 520411437

Country of ref document: SA